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Blue Nevus

Contrary to common moles, a blue nevus is not of dark brown color, but nevertheless contains melanin. It is benign, but may be considered an aesthetic problem.


Presentation

Common blue nevus and cellular blue nevus differ in appearance, although both types of blue nevi are of slate blue or dark blue color [8]. Both are most commonly observed in the head and neck region, on hand, feet and in the lumber area. They are usually present as solitary lesions and do not provoke any symptoms aside from aesthetic problems. While the vast majority of blue nevi does not undergo any alterations throughout life, the may suffer traumas. 

The common blue nevus usually measures a few millimeter in diameter, rarely exceeds 7 millimeter, is flat like a macula or slightly raised above the surrounding skin, thus acquiring the characteristics of a papula or plaque. Macula-like nevi may slowly transform into papula-like moles, but elevated moles have also been reported to flatten. Their surface is smooth. Common blue nevi do not undergo malignant transformation. This type of blue nevus is the more common form.

In contrast, the cellular blue nevus is of nodular form and may measure up to 3 centimeter in diameter and is significantly elevated above adjacent tissues. While its surface is initially also smooth, over time it may become more irregular and ulcerate. There is a possibility of malignant degeneration of large cellular blue nevi, but metastases have never been described. Such transformation may be recognized based on sudden growth and progressive superficial ulceration.

Of note, blue nevi may also be detected in mucous membranes, although they are much more common in skin. Blue nevi have been described in the oral mucosa, in the mucous membranes of the respiratory and genital tract, in the prostate and in lymph nodes [9].

Inguinal Mass
  • By contrast, the inguinal mass revealed a diffuse proliferation of highly atypical mono- to multi-nucleated large cells having abundant eosinophilic cytoplasm in the enlarged lymph node tissue.[ncbi.nlm.nih.gov]
Abdominal Mass
  • The tumor appeared as a well circumscribed but partially infiltrative upper-abdominal mass, and was heavily pigmented and consisted of a spindle or epithelioid highly cellular component with mitotic figures and tumor necroses.[ncbi.nlm.nih.gov]
Parotid Mass
  • METHODS: A 62-year-old woman presented to our clinic with sudden onset parotid mass. After a superficial parotidectomy, histologic examination of the specimen was performed.[ncbi.nlm.nih.gov]
Sparse Hair
  • Abstract A 43-year-old Japanese man presented with a 13-year history of a grayish macule measuring 7 cm in diameter with sparse hairs on the vertex.[ncbi.nlm.nih.gov]
Hypopigmented Macule
  • CASE PRESENTATION: A gradually growing and verrucous hypopigmented macule had been noticed in the right sole of a 65-year-old Japanese male since 2 years before, and it turned to be a solitary bluish to black patch with surrounding depigmentation and[ncbi.nlm.nih.gov]
Cesarean Section
  • The mass was resected during cesarean-section under the clinical impression of vaginal hemangioma. RESULT: Gross examination revealed a cystic mass measuring 6.0 4.3 3.5 cm, which was filled with dark friable material.[ncbi.nlm.nih.gov]
  • The clinical impression at this stage was vaginal hemangioma; therefore the patient was selected clinically for cesarean section due to the risk of bleeding.[diagnosticpathology.biomedcentral.com]
Dysesthesia
  • A 40-year-old woman had a 2-year history of dysesthesia and weakness in the left leg.[ncbi.nlm.nih.gov]

Workup

While blue nevi can usually be diagnosed upon visual inspection, in some cases it may be necessary to distinguish these moles from tumors and to rule out the rare malignant transformation of cellular blue nevi. In this context, differential diagnoses may be malignant melanoma, pigmented adenoma, carcinoma, hemangioma, histiocytoma, paraganglioma, dermatofibroma, pigmented metastases of other primary tumors but also xanthoma and warts. In order to distinguish these lesion, dermatoscopy may be helpful or a biopsy has to be histopathologically analyzed. This same analysis is required to differentiate common blue nevi and cellular blue nevi.

Dermatoscopical examination should reveal a homogeneous slate blue color without pigment streaks or networks or regions of aggregation [8]. In some cases, however, such findings have been reported but histopathological results nevertheless confirmed the diagnosis of a blue nevus [10].

With regards to histopathological results, common blue nevi are dominated by spindle-shaped melanocytes with little melanin and dendritic melanocytes with a high content of melanin. Also, collagen fibers and melanophages can usually be observed. Mitoses are not seen in common blue nevi, but few may be noted in the cellular type. The latter is characterized by tightly packed melanocytes of spindle or oval form and melanophages. Blue nevi are situated in the lower dermis. Sometimes, extensions into the subcutaneous fat layer may be noted.

Benign blue nevi do not show cytologic atypia or necrotic regions. These may, however, be found in cellular blue nevi that underwent malignant transformation. Typically, mitotic figures can be detected in large parts of the sample. Hyperchromasia may be seen [11].

Atypical findings have been described. For instance, blue nevi may be amelanotic. These moles are preferentially found in biopsy samples obtained from patients suffering from the Carney complex [12].

Lymphocytic Infiltrate
  • Histologic clues suggesting the possibility of a metastatic melanoma included a sparse lymphocytic infiltrate, the presence of an epithelioid component and atypia of the dendritic melanocytes.[ncbi.nlm.nih.gov]
  • The cutaneous specimen from the sole showed an aggregation of many melanophages predominantly in the middle to deep layer of dermis, associated with surrounding fibrosis, reactive vascular proliferation and CD8-positive T-lymphocytic infiltrate, covered[ncbi.nlm.nih.gov]
  • Presence of tumor-associated lymphocytic infiltrate and perineural invasion are strongly suspicious for melanoma.[acgcasereports.gi.org]

Treatment

Drug therapy is neither available nor necessary. Blue nevi are asymptomatic aesthetic flaws that very rarely may degenerate to malignancies. If any suspicion is raised to this end or if diagnosis is not clear, biopsy samples should be analyzed histopathologically as described above.

If the patient desires resection of their blue nevus, a simple excision can be performed and is most certainly curative [13]. Cellular blue nevi that underwent malignant transformation grow infiltratively and therefore require wider safety margins. If relapses occur close to the original site, re-excision should be performed.

Prognosis

Prognosis is excellent. While some blue nevi may be considered a cosmetic problem, the vast majority of this kind of moles remains unchanged and asymptomatic. There is a slight risk for malignant transformation of cellular blue nevi [7].

Etiology

Melanocytes are of ectodermal origin and develop as melanoblasts in early embryonal stages within the neural crest. Similar to other cells that emerge from this tissue, e.g., neurons, certain glia cells and those cells that later form the dentin layer of teeth, melanoblasts migrate from the neural crest to distinct areas of the forming organism during fetal development. However, some melanoblasts may either stay behind or accumulate in certain spots. These cells may form nevi after differentiation into melanocytes. While this hypothesis is widely accepted, it could not yet be proven, and there are other theories regarding the etiology of blue nevi.

One of these alternative hypotheses assumes that blue nevi develop from pluripotential dermal precursors. Such stem cells may degenerate and differentiate into a blue nevus, which would explain why the stem cell marker CD34 could,  be detected in some cells isolated from cellular blue nevi. Nevertheless, this theory is poorly accepted. The fact that stem cells mutate and differentiate into melanocyte-like cells is pure speculation.

Such nests of melanocytes, independent of their origin, may remain or form in more superficial or deeper layers of the epidermis or mucous membranes. Blue nevi are much more common in skin than in mucosa and are located in deeper positions then typical brown nevi.

Epidemiology

Blue nevi are most commonly seen in individuals of Asian origin, less frequently in Caucasians and rarely in blacks. Their prevalence has been estimated to be up to 5% in Asians, up to 2% in Caucasians and less than 1% in blacks. Of note, these prevalence rates refer to the adult population since blue nevi are seldom congenital but often develop in the course of life, mainly in people aged more than 10 years. Prevalence at birth is presumably around 0.1%.

Women are affected twice as often as men, a fact that may support the theory that female hormones influence blue nevi formation [4].

Sex distribution
Age distribution

Pathophysiology

Neither etiology nor pathogenesis of blue nevi is completely understood. As has been stated above, the most widely accepted hypothesis is that of nevi resulting from melanoblasts that did not migrate accordingly during fetal development. In this context, melanoblasts should move from the neural crest to the developing epidermis. This process may extend over weeks, melanoblasts first populate the head and neck region and subsequently the epidermis of the whole body. Most melanoblasts then differentiate into melanocytes, others rest or continue to proliferate. Melanoblast proliferation is controlled by a variety of genes and it has recently been demonstrated that guanine nucleotide-binding protein subunits Gnaq and Gna11 form part of a regulatory Gq protein. Mutations in Gnaq and Gna11 seem to enhance the activity of this Gq protein, provoke its constitutive activation, which results in excess melanoblast proliferation. This essentially renders these proteins proto-oncogenes [5]. And in fact, such mutations can be detected in the majority of blue nevi as well as in those nevi that underwent malignant transformation. There are hypotheses regarding other factors stimulating melanoblast proliferation and melanocyte counts. Most of these results have been obtained in animal studies, particularly using transgenic mice. Such experiments have shown that over-expression of hepatocyte growth factor or HRAS increases dermal melanocyte counts. It has not yet been proven that these proteins affect human melanocyte development. Interestingly, mutations associated with common brown nevi or malignant melanoma, e.g., c-kit, BRAF and NRAS, have not been detected in blue nevi [6].

Most melanocytes disappear until birth, but they tend to remain in certain areas of the body: in the head and neck region, on hand, feet and in the lumber area. These are exactly the most common sites of blue nevi. Of note, over-disappearance of melanocytes may cause other aesthetic problems such as vitiligo.

With regards to melanoblast rest or proliferation, it has been speculated that skin lesions, inflammation and other external stimuli may provoke proliferation and thus explain how nevi may develop at later points in time.

Prevention

No preventive measures can be recommended.

Summary

In general, nevi are benign alterations of the skin or mucous membranes. They may already be present at birth, but many nevi only develop throughout life. It is also possible that nevi are congenital but change their appearance at a later point in time. Usually, they are of brown to dark brown color. However, some nevi may appear bluish and such a mole is thus named blue nevus. Both blue nevi and classical brown nevi mainly consist of melanin-producing melanocytes. Their difference in color is only an optical effect: If something appears blue that means blue light, i.e., light of shorter wavelengths, is reflected by the respective object, while the remaining parts of natural light are absorbed. In contrast, if something appears brown or even black, next to no light is reflected, light of all wavelengths is absorbed. Such distinct behavior of melanin may, for instance, be due to different positions of blue and brown nevi inside the skin. Another term for blue nevus is Tièche-Jadassohn nevus or ceruloderma.

Blue nevi are more often seen in women and in people of Asian origin [1]. This fact seems to indicate that genetic factors affect the development of such moles. Blue nevi differ in appearance and may either be small, flat or maybe slightly elevated smooth moles or larger, nodular protuberances. The former is also called common blue nevus, the latter is deemed cellular blue nevus [2]. Cellular blue nevi are more likely to change their appearance over time, they may become even larger and their surface may become ulcerated and rough. Blue nevi are most commonly seen in the head and neck region, on hand, feet and in the lumber area.

Diagnosis is made upon visual examination. As has been stated above, blue nevi are benign skin alterations. However, in rare cases, cellular blue nevi may degenerate and become malignant. In order to detect such malignant transformation, biopsy and histopathological examination of nodular blue nevi that change their appearance is recommended. This procedure also allows to distinguish blue nevi from malignant melanoma, pigmented dermatofibroma, pigmented metastases of other primary tumors or pigmented warts [3].

Treatment is generally not necessary, but may be desirable if blue nevi are considered an aesthetic problem. A simple surgical intervention is required to resect the mole. Excision is highly recommended for blue nevi that are suspicious for malignant degeneration. In these cases, relapses may occur and repeated excision may be needed.

Patient Information

A blue nevus is a type of mole, similar to the more common nevus of dark brown color. It is a benign dermal lesion that usually does not require any treatment.

Causes

Blue nevi are spots of melanocytes, i.e., of pigment cells that are normally present in the outer layer of the skin, the epidermis. Contrary to classical brown nevi, blue nevi are located in deeper layers of the skin. The pigment that accounts for the darker color of moles is the same in both types of nevi, but the light is reflected in a slightly different way from distinct depths, which is why they appear in different colors.

It has been speculated that nevi develop from precursor cells that proliferate excessively, but the precise cause of blue nevi has not yet been understood.

Symptoms

There are two types of blue nevi, although they have their slate blue color in common. The common blue nevus is a small, flat to slightly raised patch of smooth surface. It rarely measures more than a few millimeters. In contrast, the cellular blue nevus is of nodular appearance and is considerably elevated above adjacent skin. They measure more than one centimeter in diameter and may grow up to three centimeter. Their surface may be more irregular and even ulcerate.

Diagnosis

Blue nevi can usually be diagnosed upon visual inspection. However, it may not be so easy to distinguish blue nevi from skin cancer or other alterations and if such a suspicion is raised, a biopsy may need to be obtained for histopathological analysis. Here, cellular patterns allow for an unequivocal diagnosis of a blue nevus.

Treatment

In most cases, treatment is not necessary. However, patients may wish for removal of their nevus because of it being an aesthetic problem. From a medical point of view, excision is only required if there is any doubt towards the benign nature of the patch.

References

Article

  1. Kunachak S, Kunachakr S, Sirikulchayanonta V, Leelaudomniti P. Dermabrasion is an effective treatment for acquired bilateral nevus of Ota-like macules. Dermatol Surg. 1996; 22(6):559-562.
  2. Knoell KA, Nelson KC, Patterson JW. Familial multiple blue nevi. J Am Acad Dermatol. 1998; 39(2 Pt 2):322-325.
  3. Phadke PA, Zembowicz A. Blue nevi and related tumors. Clin Lab Med. 2011; 31(2):345-358.
  4. Gill M, Celebi JT. B-RAF and melanocytic neoplasia. J Am Acad Dermatol. 2005; 53(1):108-114.
  5. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009; 457(7229):599-602.
  6. Yazdi AS, Palmedo G, Flaig MJ, et al. Mutations of the BRAF gene in benign and malignant melanocytic lesions. J Invest Dermatol. 2003; 121(5):1160-1162.
  7. Lambert WC, Brodkin RH. Nodal and subcutaneous cellular blue nevi. A pseudometastasizing pseudomelanoma. Arch Dermatol. 1984; 120(3):367-370.
  8. Di Cesare A, Sera F, Gulia A, et al. The spectrum of dermatoscopic patterns in blue nevi. J Am Acad Dermatol. 2012; 67(2):199-205.
  9. Dailey VL, Hameed O. Blue nevus of the prostate. Arch Pathol Lab Med. 2011; 135(6):799-802.
  10. Tsunemi Y, Saeki H, Tamaki K. Blue naevus with pigment network-like structure on dermoscopy. Acta Derm Venereol. 2008; 88(4):412-413.
  11. Loghavi S, Curry JL, Torres-Cabala CA, et al. Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature. Mod Pathol. 2014; 27(11):1468-1478.
  12. Moreno C, Requena L, Kutzner H, de la Cruz A, Jaqueti G, Yus ES. Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex. J Cutan Pathol. 2000; 27(5):218-223.
  13. Busam KJ, Woodruff JM, Erlandson RA, Brady MS. Large plaque-type blue nevus with subcutaneous cellular nodules. Am J Surg Pathol. 2000; 24(1):92-99.

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Last updated: 2018-02-09 09:57